Review
Oncogene (2006) 25, 6685–6705. doi:10.1038/sj.onc.1209934
I
B kinase complexes: gateways to NF-B activation and transcription
Claus Scheidereit1
1Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
Correspondence: Dr Claus Scheidereit, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13122 Berlin, Germany. E-mail: scheidereit@mdc-berlin.de
Abstract
Transcription factors of the NF-
B family regulate hundreds of genes in the context of multiple important physiological and pathological processes. NF-B activation depends on phosphorylation-induced proteolysis of inhibitory IB molecules and NF-B precursors by the ubiquitin-proteasome system. Most of the diverse signaling pathways that activate NF-B converge on IB kinases (IKK), which are essential for signal transmission. Many important details of the composition, regulation and biological function of IKK have been revealed in the last years. This review summarizes current aspects of structure and function of the regular stoichiometric components, the regulatory transient protein interactions of IKK and the mechanisms that contribute to its activation, deactivation and homeostasis. Both phosphorylation and ubiquitinatin (destructive as well as non-destructive) are crucial post-translational events in these processes. In addition to controlling induced IB degradation in the cytoplasm and processing of the NF-B precursor p100, nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage. Finally, IKK is engaged in cross talk with other pathways and confers functions independently of NF-B.
Keywords:
NF-kappaB, IkappaB kinase, phosphorylation, ubiquitin, chromatin, transcription
Abbreviations:
Act1, NF-B activator 1; ATM, Ataxia telangiectasia mutated; 
TrCP, transducin repeat-containing protein; BAFF, B cell-activating factor; Bcl-3, B cell lymphoma 3; Bcl-10, B cell lymphoma 10; BCMA, B cell maturation antigen; CARMA, Caspase-recruitment-domain-containing membrane-associated guanylate kinase; Cardif, CARD adaptor inducing IFN-; CBP, CREB binding protein; Cdc37, Cell division cycle 37; cIAP, Inhibitor of apoptosis protein; CIKS, connection to IKK and SAPK/JNK; CSN3, COP9 signalosome component 3; CYLD, cylindromatosis protein; Dok1, docking protein 1; EHV, Equine herpesvirus; ELKS, Protein rich in amino acids E, L, K and S; ENaC, Epithelial Na+ channel; ER
, estrogen receptor ; ERK, extracellular signal-regulated kinase; FANCA, Fanconi anemia complementation group A; FGF8, Fibroblast growth factor 8; FKBP51, FK506-binding protein 51 kDa; FOXO3a, Forkhead box transcription factor; GITR, Glucocorticoid-induced TNF receptor; HCV, Hepatitis C virus; HDAC, Histone deacetylase; HIF-2, Hypoxia-induced factor 2; HPK1, Hematopoietic progenitor kinase 1; Hsp, Heat shock protein; hTid1, Human tumorous imaginal disc 1 protein; HTLV-1, Human T-cell leukemia virus-1; Htt, Huntingtin protein; HVEM, Herpes virus entry mediator; IB, Inhibitor of kappaB binding; IKK, IB kinase; IL-1, Interleukin-1; IRAK1, Interleukin-1 receptor-associated kinase 1; IRF-7, Interferon regulatory factor-7; IRS-1, Insulin receptor substrate-1; JNK, c-Jun N-terminal kinase; KSHV, Kaposi's-sarcoma-associated herpesvirus; LMP1, Latent membrane protein; LPS, Lipopolysaccharide; LT, Lymphotoxin ; LTR, Lymphotoxin receptor; MALT, Mucosa-associated lymphoid tissue lymphoma translocation protein 1; MEKK, Mitogen-activated protein/ERK kinase kinase; NEMO, NF-B essential modifier; NF-B, Nuclear factor-kappaB; NIBP, NIK-binding protein; NIK, NF-B-inducing kinase; Nod2, Nucleotide-binding and oligomerization domain 2; PAN1, PYRIN and NACHT domain protein 1; PDK1, 3-phosphoinositide-dependent kinase 1; PIDD, p53-inducible death-domain-containing protein; PKC, Protein kinase C; PKR, Protein kinase double-stranded RNA-dependent; PMA, Phorbol myristate acetate; RANK, Receptor activator of NF-B; RANKL, Receptor activator of NF-B ligand; RFP, Ret finger protein; RIP1, Receptor interacting protein 1; RSK, Ribosomal S6 kinase; SAPK, Stress activated protein kinase; SCF, Skp1, Cdc53/Cullin1, F-box protein; Shh, Sonic hedgehog; SMRT, Silencing mediator for retinoic acid and thyroid hormone receptor; SRC-3, Steroid receptor co-activator 3; STAP-2, Signal-transducing adaptor protein-2; SUMO, Small ubiquitin-like modifier; TAB, Transforming growth factor- activated kinase 1 binding protein; TACI, Transmembrane activator and calcium modulator and cyclophilin ligand interactor; TAK1, Transforming growth factor- activated kinase 1; TANK, TNF receptor associated factor family member-associated NF-B activator; TCR, T cell receptor; TFG, Tyrosine receptor kinase-fused gene; TIFA, TRAF-interacting protein with a forkhead-associated domain; TLR, Toll-like receptor; TNF, Tumor necrosis factor; TNF-R, TNF receptor; TRADD, TNF receptor-associated death domain; TRAF, TNF receptor-associated factor; TRUSS, TNF receptor-associated ubiquitous scaffolding and signaling protein; TWEAK, TNF family member with weak apoptosis-inducing activity; vFLIP, Viral FADD-like interleukin-1--converting enzyme (FLICE/caspase 8)-inhibitory protein; YopJ, Yersinia outer protein J
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